Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1991 Oct;35(10):2046–2048. doi: 10.1128/aac.35.10.2046

Antifungal activity of HWA-138 and amphotericin B in experimental systemic candidiasis.

K M Wasan 1, K Vadiei 1, D R Luke 1, A Keyhani 1, R A White 1, T J McQueen 1, R Mehta 1, G Lopez-Berestein 1
PMCID: PMC245323  PMID: 1759826

Abstract

HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice.

Full text

PDF

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Armstrong M., Jr, Needham D., Hatchell D. L., Nunn R. S. Effect of pentoxifylline on the flow of polymorphonuclear leukocytes through a model capillary. Angiology. 1990 Apr;41(4):253–262. doi: 10.1177/000331979004100401. [DOI] [PubMed] [Google Scholar]
  2. Bidani A. K., Churchill P. C., Packer W. Theophylline-induced protection in myoglobinuric acute renal failure: further characterization. Can J Physiol Pharmacol. 1987 Jan;65(1):42–45. doi: 10.1139/y87-008. [DOI] [PubMed] [Google Scholar]
  3. Brunner L. J., Vadiei K., Iyer L. V., Luke D. R. Prevention of cyclosporine-induced nephrotoxicity with pentoxifylline. Ren Fail. 1989;11(2-3):97–104. doi: 10.3109/08860228909066950. [DOI] [PubMed] [Google Scholar]
  4. Burgess J. L., Birchall R. Nephrotoxicity of amphotericin B, with emphasis on changes in tubular function. Am J Med. 1972 Jul;53(1):77–84. [PubMed] [Google Scholar]
  5. Crocket K. V., Lackie J. M., Rogers A. A. Effect of pentoxifylline on neutrophil behaviour: stimulation of movement without adhesion changes. Biomed Pharmacother. 1988;42(2):117–120. [PubMed] [Google Scholar]
  6. Dinarello C. A. Interleukin-1. Rev Infect Dis. 1984 Jan-Feb;6(1):51–95. doi: 10.1093/clinids/6.1.51. [DOI] [PubMed] [Google Scholar]
  7. Hammerschmidt D. E., Kotasek D., McCarthy T., Huh P. W., Freyburger G., Vercellotti G. M. Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor. J Lab Clin Med. 1988 Aug;112(2):254–263. [PubMed] [Google Scholar]
  8. Heidemann H. T., Gerkens J. F., Jackson E. K., Branch R. A. Effect of aminophylline on renal vasoconstriction produced by amphotericin B in the rat. Naunyn Schmiedebergs Arch Pharmacol. 1983 Sep;324(2):148–152. doi: 10.1007/BF00497021. [DOI] [PubMed] [Google Scholar]
  9. Heidemann H. T., Müller S., Mertins L., Stepan G., Hoffmann K., Ohnhaus E. E. Effect of aminophylline on cisplatin nephrotoxicity in the rat. Br J Pharmacol. 1989 Jun;97(2):313–318. doi: 10.1111/j.1476-5381.1989.tb11956.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hendeles L., Weinberger M. Theophylline. A "state of the art" review. Pharmacotherapy. 1983 Jan-Feb;3(1):2–44. doi: 10.1002/j.1875-9114.1983.tb04531.x. [DOI] [PubMed] [Google Scholar]
  11. Lopez-Berestein G., Mehta R., Hopfer R. L., Mills K., Kasi L., Mehta K., Fainstein V., Luna M., Hersh E. M., Juliano R. Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin B. J Infect Dis. 1983 May;147(5):939–945. doi: 10.1093/infdis/147.5.939. [DOI] [PubMed] [Google Scholar]
  12. Luke D. R., Berens K. L., Verani R. R. Role of vascular decongestion in ischemic acute renal failure defined by postinsult administration of pentoxifylline. Ren Fail. 1989;11(4):187–194. doi: 10.3109/08860228909054930. [DOI] [PubMed] [Google Scholar]
  13. Luke D. R., Wasan K. M., McQueen T. J., Lopez-Berestein G. Enhancement of the treatment of experimental candidiasis with vascular decongestants. J Infect Dis. 1990 Jul;162(1):211–214. doi: 10.1093/infdis/162.1.211. [DOI] [PubMed] [Google Scholar]
  14. Luke D. R., Wasan K. M., Verani R. R., Brunner L. J., Berens K. L., Vadiei K., Lopez-Berestein G. Attenuation of amphotericin-B nephrotoxicity in the candidiasis rat model. Nephron. 1991;59(1):139–144. doi: 10.1159/000186533. [DOI] [PubMed] [Google Scholar]
  15. Medoff G., Brajtburg J., Kobayashi G. S., Bolard J. Antifungal agents useful in therapy of systemic fungal infections. Annu Rev Pharmacol Toxicol. 1983;23:303–330. doi: 10.1146/annurev.pa.23.040183.001511. [DOI] [PubMed] [Google Scholar]
  16. Movat H. Z., Cybulsky M. I., Colditz I. G., Chan M. K., Dinarello C. A. Acute inflammation in gram-negative infection: endotoxin, interleukin 1, tumor necrosis factor, and neutrophils. Fed Proc. 1987 Jan;46(1):97–104. [PubMed] [Google Scholar]
  17. Norman A. W., Spielvogel A. M., Wong R. G. Polyene antibiotic - sterol interaction. Adv Lipid Res. 1976;14:127–170. [PubMed] [Google Scholar]
  18. Rob P. M., Fandrey J., Jelkmann W. Theophylline: a new concept of nephroprotection in acute cyclosporin A nephrotoxicity? Klin Wochenschr. 1989 Jun 15;67(12):648–648. doi: 10.1007/BF01718153. [DOI] [PubMed] [Google Scholar]
  19. Sullivan G. W., Carper H. T., Novick W. J., Jr, Mandell G. L. Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect Immun. 1988 Jul;56(7):1722–1729. doi: 10.1128/iai.56.7.1722-1729.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Tolins J. P., Raij L. Adverse effect of amphotericin B administration on renal hemodynamics in the rat. Neurohumoral mechanisms and influence of calcium channel blockade. J Pharmacol Exp Ther. 1988 May;245(2):594–599. [PubMed] [Google Scholar]
  21. Vadiei K., Brunner L. J., Luke D. R. Effects of pentoxifylline in experimental acute renal failure. Kidney Int. 1989 Sep;36(3):466–470. doi: 10.1038/ki.1989.218. [DOI] [PubMed] [Google Scholar]
  22. Wasan K. M., Vadiei K., Lopez-Berestein G., Verani R. R., Luke D. R. Pentoxifylline in amphotericin B toxicity rat model. Antimicrob Agents Chemother. 1990 Feb;34(2):241–244. doi: 10.1128/aac.34.2.241. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES